Naphtheridinone- and pyridooxazinone-pyridone compounds, cardiotonic compositions including same, and their uses

ABSTRACT

This invention relates to substituted pyridooxazinone and naphtheridone pyridones which are useful as cardiotonic agents for the treatment of congestive heart failure, to methods for increasing cardiac contractility using said compounds, and pharmaceutical compositions including the same.

a continuation-in-part of U.S. Ser. No. 47,394, filed May 8, 1987,andPCT/US88/01504 filed May 4, 1988.

FIELD OF INVENTION

This invention relates to diazabicyclic substituted pyridones which areuseful as cardiotonic agents for the treatment of congestive heartfailure. This invention also relates to methods for increasing cardiaccontractility using said compounds, and pharmaceutical compositionsincluding said compounds.

Congestive heart failure is a life-threatening condition in whichmyocardial contractility is depressed so that the heart is unable toadequately pump the blood returning to it. Normal pathologic sequelaeinclude decreased cardiac output, venous pooling, increased venouspressure, edema, increased heart size, increased myocardial walltension, and eventually cessation of contractility.

REPORTED DEVELOPMENTS

Drugs which increase the tone of the heart muscle are described ashaving positive inotropic activity and are characterized as cardiotonicagents. Digitalis glycosides have long been used to increase myocardialcontractility and reverse the detrimental changes seen in congestiveheart failure. More recently, dopamine, dobutamine, and amrinone havebeen used to provide necessary inotropic support for the failing heart.

Cardiotonic agents which are described as having positive inotropicactivity include the 5-pyridyl substituted pyridones disclosed in U.S.Pat. Nos.: 4,004,012; 4,072,746; 4,107,315; 4,137,233; 4,199,586 and4,271,168; in GB 2070606A; and in PCT published Appl. No.pCT/CH81/00023. Other cardiotonic drugs include the diazacyclicsubstituted carbostyril compounds disclosed in U.S. Pat. Nos. 4,414,390and 4,415,572, cardiotonic pyridyl substituted carbostyril compoundsdisclosed in EPO application Serial No. 84308925.1, and cardiotonic5-substituted-1,6-naphthyridine2(1H)-one compounds disclosed in U.S.Pat. No. 4,657,915.

Cardiotonic bicyclic heteroaryl-5-substituted pyridyl compounds aredisclosed in PCT published application Serial Nos. PCT/US83/01285 andPCT/US87/01489 (WO 88/00188); and, cardiotonicdiazheterocyclic-5-substituted pyridyl compounds are disclosed in U.S.Pat. Nos. 4,432,979, 4,514,400 and 4,539,321. Each of the aforementionedis assigned to the same assigned as the present application.

SUMMARY OF THE INVENTION

The present invention relates to naphtheridone- andpyridooxazinone-pyridone compounds which are useful for increasingcardiac contractility in humans and other mammals. The compounds of thepresent invention include compounds of Formula I: ##STR1## wherein:

A is -C=or -N=;

B is -C=C-, -C=N- or -N=C-; provided that A or B represents anitrogen-containing group;

X is --(CR₄ R₅)_(a) --(0 )_(b) --(CR₆ R₇)_(c) --;

a and c are 0, 1 or 2;

b is 0 or 1;

provided that a +b +c =1, 2 or 3;

R is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, nitro, halo, cyano,carbamoyl, alkyl carbamoyl, formyl, aminoalkylene or amino;

R₁, R₂, R₃, R₅, R₆ and R₇ are hydrogen, alkyl, or aralkyl;

R₄ is hydrogen, alkyl, aryl, or aralkyl;

geminal R₆ and R₇ groups may together form a spiro substituent,-(CH₂)d-, where d is 2 to 5; and pharmaceutically acceptable saltsthereof.

This invention relates also to methods for increasing cardiaccontractility using pharmaceutical compositions including an effectiveinotropic amount of a compound of Formula I above.

DETAILED DESCRIPTION

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

"Alkyl" means a saturated aliphatic hydrocarbon which may be eitherstraight or branched-chained containing from about 1 to about 6 carbonatoms.

"Lower alkyl" means an alkyl group as above, having 1 to about 4 carbonatoms.

"Aralkyl" means an alkyl group substituted by an aryl radical where arylmeans a phenyl or phenyl substituted with one or more substituents whichmay be alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkylamino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkyl mercaptyl,carboalkyl or carbamoyl. The preferred aralkyl groups are benzyl orphenethyl.

"Alkyl carbamoyl" means a carbamoyl group substituted by one or twoalkyl groups. Preferred groups are the lower alkyl carbamoyl groups.

"Hydroxyalkyl" means an alkyl group substituted by a hydroxy group.Hydroxy lower alkyl groups are preferred. Exemplary preferred groupsinclude hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and3-hydroxypropyl.

"Alkoxy" means an alkyl-oxy group in which "alkyl" is as previouslydescribed. Lower alkoxy groups are preferred. Exemplary groups includemethoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.

"Alkoxyalkyl" means an alkyl group as previously described substitutedby an alkoxy group as previously described.

"Aminoalkylene" means a group of the formula --(CH₂)_(n) ----NH₂ where nis 1 to about 6. The preferred groups are the lower alkylene aminogroups wherein lower alkylene groups are of 1 to about 4 carbon atoms.The most preferred amino alkylene group is aminomethylene.

Certain of the compounds of the present invention may exist in enolic ortautomeric forms, and all of these forms are considered to be includedwithin the scope of this invention.

The compounds of this invention may be useful in the form of the freebase, in the form of salts and as a hydrate. All forms are within thescope of the invention. Acid addition salts may be formed and are simplya more convenient form for use; and in practice, use of the salt forminherently amounts to use of the base form. The acids which can be usedto prepare the acid addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically acceptablesalts, that is, salts whose anions are non-toxic to the animal organismin pharmaceutical doses of the salts, so that the beneficial cardiotonicproperties inherent in the free base are not vitiated by side effectsascribable to the anions. Although pharmaceutically acceptable salts ofsaid basic compound are preferred, all acid addition salts are useful assources of the free base form even if the particular salt per se isdesired only as an intermediate product as, for example, when the saltis formed only for purposes of purification and identification, or whenit is used as an intermediate in preparing a pharmaceutically acceptablesalt by ion exchange procedures. Pharmaceutically acceptable saltswithin the scope of the invention are those derived from the followingacids: mineral acids such as hydrochloric acid, sulfuric acid,phosphoric acid and sulfamic acid; and organic acids such as aceticacid, citric acid, lactic acid, tartaric acid, malonic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclohexylsulfamic acid quinic acid, and thelike. The corresponding acid addition salts comprise the following:hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate,tartarate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.

The acid addition salts of the compounds of this invention are preparedeither by dissolving the free base in aqueous or aqueous-alcoholsolution or other suitable solvents containing the appropriate acid andisolating the salt by evaporating the solution, or by reacting the freebase and acid in an organic solvent, in which case the salt separatesdirectly or can be obtained by concentration of the solution.

A preferred class of cardiotonic compounds of this invention isdescribed by Formula I wherein the bicyclic ring of the molecule isrepresented by Formulae IIa-IIc, IIIa-IIIc or IVa-IVc, presented below:##STR2## wherein:

R₃, R₄, R₅, and R₆ and R₇ are as described above and a and c are 1 or 2.

A more preferred class of compounds are of Formula I--IV above, whereinR is cyano, R₂ is lower alkyl and R₁ R₃, R₄, R₅, R₆, R₇ are hydrogen orlower alkyl.

Most preferred compounds are those disclosed by Formula I, wherein R iscyano, R₁ is hydrogen, R₂ is methyl and R₃ through R₇ are hydrogen ormethyl.

A special embodiment of the invention comprises compounds of FormulaIIIc where b+c add up to 2.

A further special embodiment comprises compounds of Formula I where R₆and R₇ form a spiro ring system, two examples of which are shown byFormula V and Va below: ##STR3##

Compounds of this invention may be prepared by constructing the pyridonering substituent on the bicyclic portion of the compound as shown belowin Scheme I. ##STR4##

Halogenation of a compound of Formula VI results in the correspondinghalogenation product VII. Bromination is a preferred reaction whichoccurs on the pyrido ring of the bicyclic compound in the position parato the nitrogen of the lactam. Bromination can be carried out withbromination reagents known in the art. A preferred method isN-bromosuccinimide in a polar, non-protic solvent such as DMF.Subsequent alkylation or aralkylation of the lactam nitrogen with anappropriate alkylating agent results in the adduct of Formula VIII,which is oxopropylated by treatment with an acylated isopropenyl reagentand catalyst. A preferred catalytic system comprises the use oftri-o-tolylphosphine, palladium acetate, and tributyltin methoxide.Preferred reaction conditions comprise using a non-polar solvent such asbenzene and heating the reaction to a temperature which results in thepreparation of the product in a reasonably short period of time of about10 minutes to about two days. A preferred temperature range is about 75to about 80° C. Condensation of the compound of Formula IX withN,N-dimethylformamide dimethylacetal results in the alpha, betaunsaturated keto-compound X. Cyclization to the compound of Formula Iais accomplished by treatment with an appropriate amido-containingnucleophile which adds 1,2 to the unsaturated ketone and condenses withthe ketone eliminating dimethylamine and water. A preferred nucleophileis sodium cyanoacetamide which may be prepared by the reaction of sodiumhydride with cyanoacetamide or sodium ethoxide in ethanol. Compound Xmay also be condensed with nitroacetamide resulting in the compound ofFormula I where R is NO₂. The cyclization reaction is conductedpreferably at elevated temperature such as 70 to about 90° C., underinert conditions in a polar medium such as DMF or ethanol.

The cyano substituent in Formula Ia may be converted to othersubstituents defined for R in Formula I. For example the cyano group maybe hydrolyzed to the acid which in turn can be esterified or convertedto the amide. The ester may be converted by known methods to formylwhich in turn can be reduced to the alkyl or hydroxyalkyl substituent.The alkoxyalkyl may be formed from the hydroxyalkyl.

The nitro-containing compound may be reduced to the amino compound fromwhich the hydroxy and halo substituted compounds may be formed. Thesemethods and reaction conditions would vary, of course, depending on thedesired substituent and the substituent present, and are known to oneskilled in the art.

The starting materials useful for the preparation of the compounds ofthis invention are known, can be prepared by known methods or preparedin accordance with the reaction sequences described below. For compoundsof Formula I wherein b is 1, the bicyclic portion of the compound may beprepared according to the following reaction sequences.

When 2amino-3hydroxypyridine is treated with sodium hydride followed byring closure with a a-haloacetate ester of the formula ##STR5## thepyridooxazinones are formed. ##STR6## When the seven member-containingbicyclic ring is desired, the reaction is carried out using thehalopropinate as shown below. ##STR7##

The five member-containing bicyclic ring is prepared by reacting2-amino-3-hydroxypyridine with either phosgene orN,N-carbonyldiimidazole as shown below. ##STR8##

Those compounds where the oxygen atom of the pyridooxazinone ring is notdirectly on the pyridine ring are prepared from a 22-aminonnicotinicacid or ester, reducing the latter to the corresponding alcohol andcyclizing as above. These reactions are depicted inn Schemes II and IIabelow. ##STR9##

When the starting pyridine is 3-amino-4-hydroxypyridine or2-hydroxy-3-aminopyridine then the corresponding pyridooxazinone isprepared as shown below. ##STR10##

Compounds wherein R₃ is other than hydrogen are prepared from N-R₃-substituted amino-pyridines.

For compounds of Formula I wherein b is 0, the bicyclic portion of thecompounds may be prepared according to one of the reaction sequencesdepicted in Scheme III below. Treatment of the33-carbonyl-2trimethylmethylamidopyridine compound depicted in SchemeIII with a triphenylphosphine ylide reagent yields the unsaturated ylideaddition product. The ylide chosen for the addition reaction may includeR6 and R7 substituents other than hydrogen. Furthermore, the R8substituent on the ylide determines the size of the resultant saturatedring of the bicyclic end product as shown in Scheme III. Hydrogenationof the ylide addition product and acidic cyclization to the lactamprovides the bicyclic system. ##STR11##

N-alkylation and halogenation of the bicyclic ring proceeds in the samemanner as described for the oxygencontaining bicyclic rings discussedabove.

Introduction of a spiro group into the bicyclic rings wherein the carbonatom alpha to the lactam carbonyl is unsubstituted is accomplished byreacting the intermediate compound of Formulae VIII with a strong basesuch as lithium diisopropyl amide and a suitable dibromoalkane such as1,2-dibromoethane or 1,4-dibromobutane.

Specific examples of the preparation of compounds of this invention aredescribed below.

EXAMPLE 1 The Preparation Of7-[3',-CYANO-6',-METHYL-2',-OXO-(1H)PYRIDIN-5',-YL]-4-METHYL-2H-PYRIDO[3,2]-1.4-OXAZIN-3(4H)-ONE Step 1.7-Bromo-2H-pyrido[3,2-b]b 1,4-oxazin-3(4H)-one

To a solution of 5.6g 2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one dissolved in85 ml of DMF under nitrogen is added 7.96 g NBS in 50 ml of DMF. This isallowed to stir at room temperature overnight. To this is added 35 ml ofwater and chilled. The solid material which separates is filtered andwashed with 3x100 ml H₂ O. This is then dried in a vac oven at 70°C. andthen used directly in the next step.

Step 2. 4-Methyl-7-bromo-2H-pyrido[3,22-b]1,4-oxazin-3(4H)-one

To a suspension of 5g of 7-bromo-2H-pyrido[3,2-b]-1,4oxazin-3(4H)-one(0.022 mole) in 90 ml of THF is added 24 ml of LiN(TMS)₂ (0.024 mole) inTHF. The homogenous solution is maintained under nitrogen at roomtemperature for 20 min., 3.03g (0.024 mole) of dimethylsulfate is addedand the reaction mixture allowed to stir overnight. The reaction mixtureis then quenched with 20 ml of sat. ammonium chloride and extracted with3×80 ml ethyl acetate The ethyl acetate is then washed with 3×30 ml sat.ammonium chloride, dried over sodium sulfate and concentrated to obtainoff white product which is used directly in the next step. Step 3.4-Methyl-7-(2'-oxopropyl)

-2H-pyrido[3.2-b1-1.4-oxazin-3(4H)-one4-Methyl-7-bromo-2H-pyrido[3,2-b]-l,4-oxazin-3(4H)-one (3 g) (0.012mole) in 80 ml of benzene is treated with 365 mg tri-o-tolylphosphine,138 mg palladium acetate, 1.87 g (0.018 mole) of isopropenyl acetate and5.9 g (0.18 mole) of tributyltin methoxide. The mixture is heated to 70C for 25 hours. The reaction mixture is then quenched with 20 ml sat.ammonium chloride and diluted with 50 ml ethyl acetate. The organicphase separates, dried over sodium sulfate and concentrated to dryness.The residue is dissolved in methylene chloride, washed with sat. KFsolution, filtered through a cotton plug, dried over sodium sulfate andconcentrated to dryness to obtain crude product. This is chromatographedusing 200×60 mm SiO₂, EtOAc (100%) as eluent. The desired product isidentified by NMR and used directly in the next step. Step 4.4-Methyl-7-[1'-N,N-dimethylamino-3'-oxobuten-2'-yl]-2H-pyrido[3,2-b1-1,4,-oxazin-3(4H)-one

To 1.05 g (0.0047 mole) of 4-methyl-7-(2'-oxopropyl)-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one suspended in 10 ml of dimethylformamidedimethylacetal is added 1 ml of pyridine. This is then heated undernitrogen at 70° C for 5 hours. The reaction mixture is then concentratedin vacuo to leave an dark oily solid. Trituration with methylenechloride gives a pale yellow solid which is filtered off and identifiedto be desired product by NMR. This is then used directly in the nextstep.

Step 5. 7-[3,-Cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-b4-methyl-2H-pyrido [3,2-b]-1,4-oxazin-3(4H)-one

Sodium hydride (87 mg/oil) is washed with pet. ether and suspended in 4ml of DMF under nitrogen. To this is added 166 mg of cyanoacetamide in 3ml of DMF and the mixture stirred for about 5 min. A solution of 500 mgof 4-methyl-7-[1'-N,N-dimethylamino-3'-oxobuten-2'-yl]-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one in 4 ml of DMF is added to the mixture andheated under nitrogen at 80° C for 4.5 hours. This is then diluted with15 ml of sat. ammonium chloride and extracted with 4×40 ml of ethylacetate, dried over sodium sulfate and concentrated in vacuo. (M.P. 350°C.)

Calc'd. C, 59.36; H, 4.25; N, 18.46

Found C, 59.44; H, 4.32; N, 18.56

EXAMPLE 2

When 2H-pyrido [3,2-b]-1,4-oxazin-3-(4H)-one of Example 1, Step 1 isreplaced with the compounds of Table I below, then the correspondingproduct is obtained.

                  TABLE I                                                         ______________________________________                                        2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one                                         2H-pyrido[4,3-b]-1,4-oxazin-3(4H)-one                                         2H-pyrido[2,3-b]-1,4-oxazin-3(4H)-one                                         4H-pyrido[2,3-d][1,3]oxazin-2(1H)-one                                         4H-pyrido[3,4-d][1,3]oxazin-2(1H)-one                                         4H-pyrido[3,2-d][1,3]oxazin-2(1H)-one                                         oxazolo[4,5-b]pyridin-2(3H)-one                                               oxazolo[4,5-c]pyridin-2(3H)-one                                               oxazolo[5,4-b]pyridin-2(3H)-one                                               2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one                               2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one                               2,3-dihydropyrido[2,3-b][1,4]oxazepin-4(5H)-one                               3,5-dihydropyrido[2,3-e]-1,4-oxazepin-2-(1H)-one                              3,5-dihydropyrido[3,4-e]-1,4-oxazepin-2-(1H)-one                              3,5-dihydropyrido[3,2-e]-1,4-oxazepin-2-(1H)-one                              4,5-dihydropyrido[2,3-d]-1,3-oxazepin-2(1H)-one                               4,5-dihydropyrido[3,4-d]-1,3-oxazepin-2(1H)-one                               4,5-dihydropyrido[3,2-d]-1,3-oxazepin-2(1H)-one                               ______________________________________                                    

EXAMPLE 3 The preparation of6-[3'-nitro-6'-methyl-2-oxo(1H)pyridin-5'-YL]-3-methyl-oxazolo[4,5-b]Pyridin-2(3H)-one Step 1. 6-Bromo-oxazolo[4.5-b1pyridin-2(3H)-oneTo a solution of 5.07 g oxazolo[4,5-b]pyridin-2(3H)-one dissolved in 85ml of DMF under nitrogen is added 7.46 g NBS in 50 ml of DMF. This isallowed to stir at room temperature overnight. To this is added 35 ml ofwater and chilled. The solid material which separates is filtered andwashed with 3×100 ml H₂ O. This is then dried in a vac oven at 70° C andthen used directly in the next step. Step 2.3-Methyl-6-bromo-oxazolo[4.5-b1pyridin-2(3H)-one

To a suspension of 4.7 g of 6-bromo-oxazolo[4,5-b]- pyridin-2(33H)-one(0.022 mole) in 90 ml of THF is added 24 ml of LiN(TMS)₂ (0.024 mole) inTHF. The homogenous solution is maintained under nitrogen at roomtemperature for 20 min., 3.03 g (0.024 mole) of dimethylsulfate is addedand the reaction mixture allowed to stir overnight. The reaction mixtureis then quenched with 20 ml of sat. ammonium chloride and extracted with3×80 ml ethyl acetate. The ethyl acetate is then washed with 3×30 mlsat. ammonium chloride, dried over sodium sulfate and concentrated toobtain off white product which is used directly in the next step.

Step 3. 3-Methyl-6-(2,-oxopropyl)-oxazolo[4,5-b]pyridin-2-(3H)-one

3-Methyl-6-bromo-oxazolo[4,5-b]pyridin-2(3H)-one (2.58 g) (0.012 mole)in 80 ml of benzene is treated with 365 mg tri-o-tolylphosphine, 138 mgpalladium acetate, 1.87 g (0.018 mole) of isopropenyl acetate and 5.9 g(0.18 mole) of tributyltin methoxide. This is sealed in a high pressuretube and heated to 70° C for 25 hours. The reaction mixture is thenquenched with 20 ml sat. ammonium chloride and diluted with 50 ml ethylacetate. The organic phase separates, dried over sodium sulfate andconcentrated to dryness. The residue is dissolved in methylene chloride,washed with sat. KF solution, filtered through a cotton plug, dried oversodium sulfate and concentrated to dryness to obtain crude duct. This ischromatographed using 200×60 mm SiO₂, EtOAc (100%) as eluent. Thedesired product is identified by NMR and used directly in the next step.

Step 4. 3-Methyl-6-[1,-N,N-dimethylamino-3,-oxobuten-2'-yl]-oxazolo[4,5-b]pyridin 2(3H)-one

To 1.47 g (0.007 mole) of 3-methyl-6-(2'-oxopropyl)oxazolo[4,5-b]pyridin-2(3H)-one suspended in 15 ml of dimethylformamidedimethylacetal is added 1.5 ml of pyridine. PG,21 This is then heatedunder nitrogen at 70° C for 5 hours. The reaction mixture is thenconcentrated in vacuo to leave a dark oily solid. Trituration withmethylene chloride gives a solid which is filtered off and identified tobe desired product by NMR This is then used directly in the next step.

Step. 5.6-[3'-Nitro-6,-methyl-2,-oxo-(1H)pyridin-5,-yl]-3-methyl-oxazolo[4,5-b]pyridin-2(3H)-one

Sodium hydride (174 mg/oil) is washed with pet. ether and suspended in10 ml of DMF under nitrogen. To this is added 330 mg of nitroacetamidein 6 ml of DMF and the mixture stirred for about 5 min. A solution of940 mg of3-methyl-6-[1'-N,N-dimethylamino-3'-oxobuten-2'-yl]-oxazolo[4,5-b]pyridin-2(3H)-onein 10 ml of DMF is added to the mixture and heated under nitrogen at 80°C. for 4.5 hours. This is then diluted with 30 ml of sat. ammoniumchloride and extracted with 4×75 ml of ethyl acetate, dried over sodiumsulfate and concentrated in vacuo.

EXAMPLE 4

When nitroacetamide is replaced in Example 3, Step 5 by cyanoacetamidethen the product prepared is6-[3,-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]3-mmethyl-2,-oxo-(1H)pyridin-5,-yl]-3-methyl-oxazolo[4,5-b]-

EXAMPLE 5

When dimethylsulfate is replaced in Examples 1 and 3, Step 2, withbenzylbromide, then4-benzyl-7-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one and3-benzyl-6-bromo-oxazolo[4,5-b]pyridin-2(3H)-one are produced.

EXAMPLE 6

Following the procedures of Examples 1-5, the following compounds may beprepared:

7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4-methyl-2H-pyrido[4,3-b]-1,4-oxazin-3(4H)-one.

7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4- methyl-2H-pyrido[2,3-b]-1,4-oxazone.

6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-3methyloxazolo[4,5-b]pyridin-2(3H)-one.

6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-3methyloxazolo[4,5-c]pyridin-2(3H)-one.

6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-3methyloxazolo[5,4-c]pyridin-2(3H)-one.

6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-1-methyl-4H-pyridopyrido[2,3-d][1,3]oxazin-2(1H)-one.

8-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one.

8-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-5-methyl--2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one.

7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-1-methyl-3,5-dihydropyridin[2,3-e]-1,4-oxazepin-4(1H)-one.

7-[3'-amino-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4- methyl-2H-pyrido[3,22-b]-1,4oxazin-3(4H)-one.

7-[3'-chloro-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4-methyl-2H-pyrido[3,2-b]1,4-oxazin-3(4H)-one.

7-[3'-methoxymethyl-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4methyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one.

7-[3',6'-dimethyl-2'-oxo-(1H)pyridin-5'-yl]-4-methyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one.

7-[3,-cyano-6,-methyl-2'l-oxo-(1H)pyridin-5'-yl]4-ethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one.

7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-2H-pyrido[3,2-b]1,4-oxazin-3(4H)-one.

7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]2,2,4-trimethyll-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one.

(M.P. >300° C.)

Calc'd. C, 61.93; H, 4.55; N, 18.06

Found C, 61.64; H, 4.95; N, I7.14

Confirmed by high resolution mass spec.

7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'yl]-2-methyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one. (M.P. >310° C.)

Calc'd. C, 62.95; H, 4.47; N, 17.27

Found C, 62.61; H, 5.18; N, 16.94

7-[3,-cyano-6,-methyl-2,-oxo-(1H)pyridin-5,yl]-2,4-dimethyl-2H-pyrido[3,2-b]-I,4-oxazin-3(4H)-one.

(M.P. >300° C)

Calc'd. C, 61.04; H, 4.64; N, 17.79

Found C, 61.08; H, 4.72; N, 17.65

As the quarterhydrate

7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'yl]-2-phenyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one.

(M.P. 224-246° C.)

Calc'd. C, 66.92; H, 4.42; N. 14.87

Found C, 66.81; H, 4.84; N, 14.52

As the quarterhydrate

EXAMPLE 7 THE PREPARATION OF6-[3'-CYANO-6'-METHYL-2'-OXO-(1H)PYRIDIN-5'-YL]-3,4-DIHYDRO-METHYL-1,8-NAPHTHERIDIN-2(1H)-ONEStep 1. 2-(Piyaloylamino1ovridine

A solution of pivaloyl chloride (96 g) in methylene chloride (200 ml) isadded dropwise to a cooled mixture of 2-aminopyridine (50 g) andtriethylamine (108 g) in methylene chloride (650 ml). The reactionmixture is stirred overnight at RT and poured into water which isbasified and the organic layer separated and concentrated in vacuo.Hexane is added to the oil which results in the precipitation of acrystalline solid which is filtered and the solid taken up in aqueousacid. The desired pyridine compound is recrystallized as a whitecrystalline solid.

5 Step 2. 3-Formyl-2-(pivaloylamino)ovridine

N-Butyl lithium (112 ml) is added dropwise to a stirred solution of thepyridine prepared according to step 1 (20 g) in THF (250 ml) at -78° C.The reaction mixture is warmed to 0° C. for about 4 hours and cooled to-78° C. Dimethyl formamide (30 ml) is added to the cooled reactionmixture and the mixture stirred overnight at RT. The reaction mixture isquenched with sat'd aqueous NH₄ Cl and diluted with ethyl acetate. Theorganic layer is separated, concentrated and treated with aqueous acid.The aqueous layer is washed with ethyl acetate, brought to a neutral pHand extracted with ethyl acetate. The organic extract is dried,concentrated in vacuo and cooled, resulting in the formation of acrystalline material which is further purified on a silica gel column toafford a white crystalline solid used in the next step.

Step 3. 3-(2-Carbomethoxyvinyl)-2-(pivaloylamino)-pyridine

A solution of the formyl compound of step 2. above (9.8 g) in methylenechloride (100 ml) is added dropwise to a solution ofcarbomethoxymethylide triphenylphosphine (16 g) in methylene chloride(125 ml). The reaction mixture is stirred at reflux overnight, cooled toRT, concentrated in vacuo and petroleum ether added. The etherealsolution is cooled resulting in the precipitation of the desiredmaterial as a white crystalline solid, M.P 148-150° C.

Step 4. 3.4-Dihydro-1.8-naphtheridin-2(1H)-one

A solution of the carbomethoxy vinyl compound of step 3. above (9 ), 10%Pd on C in ethanol (400 ml) is introduced into a Parr apparatus andstirred under hYdrogen until the reaction is complete. The reactionmixture is filtered, the filtrate concentrated in vacuo, and the residuedissolved in 6 N HCl and stirred at 110° C overnight. The reactionmixture is neutralized, extracted with chloroform and dried, filteredand concentrated in vacuo. The resulting solid is chromatographed onsilica gel resulting in a purified white crystalline product, M.P.160-162° C.

Step 5. 6-Bromo-3.4-dihydro-1.8-naphtheridin-2(1H)-one

A solution of N-bromosuccinimide (3.7 g) in dimethyl formamide (70 ml)is added dropwise to a stirring solution of the naphtheridine of step 4.above maintained at about -10° C. The reaction mixture is warmed to RTand stirred overnight. Water is added to the mixture and the resultingsuspension is stirred for 15 min., filtered, the filtered solid washedwith water and recrystallized from DMF to yield the desired product as awhite crystalline solid.

Step 6. 6-Bromo-3,4-dihydro-1methyl--1,8naphteridin-2(1H)-one

A 1M solution of lithium bistrimethylsilylamide in THF (6.6 ml) is addeddropwise to a stirring solution of the bromide from step 5 above (1.2 g)in THF (100ml) at 0° C. The mixture is allowed to warm to RT and stirredfor about 1 hour. Dimethyl sulfate (0.8g) is added to the mixture whichis stirred for about 2 hours. The reaction is quenched with sat'daqueous NH₄ Cl and the organic layer is separated, washed with sat'd NH₄Cl solution, concentrated in vacuo, and the residue taken up inchloroform. The chloroform solution is washed with water, dried,concentrated and chromatographed on silica gel to yield the desiredproduct as a clear white crystalline solid, M.P.=78-80° C.

Step 7. 6-(2-oxopropyl)-3,4-dihydro-1-methyl-1,8naphtheridin-2(1H)-one

Para-triorthotolylphosphine (0.1 g), palladium acetate (0.05g),2-acetoxypropene (0.6g) and tributyltin methoxide (2g) are added to asolution of the bromide from step 6 above (1g) in benzene (40ml), andthe resulting reaction mixture is stirred under N₂ at 80° C. for about2.5 hours. The mixture is filtered, concentrated in vacuo, and theresidue taken up in acetonitrile. The solution is filtered and thefiltrate washed with hexanes. The acetonitrile layer is dried, filteredand concentrated in vacuo yielding the desired product as a crystallinesolid, M.P.=93-95° C.

Step 8.6-(1-N,N'-Dimethylamino-3-oxobuten-2yl)-2-oxopropyl)-3,4-dihydro-methyl-1,80-naphtheridin2(1)-one

Dimethylformamide dimethylacetal (4.6 ml) is added to a solution of thecompound of step 7. above (0.7g) in methylene chloride (25ml) and thereaction mixture stirred under nitrogen overnight. The mixture wasevaporated yielding the desired product as an oil which is used as is inthe next step.

Step 9.6-[3'-Cyano-6'-methyl-2'-oxo-(H)pyridin-5'-yl]-3,4-dihydro-1-methyl-1,8-naphtheridin-2(1H)-one

A solution of the dimethylamino enamine of step 8 above (0.7 g) inabsolute ethanol (45 ml) is added to a mixture prepared by adding a 21%solution of sodium methoxide in ethanol(1.5 ml) to a solution ofcyanoacetamide (0.3 g) in ethanol (25ml). The reaction mixture isstirred at reflux under nitrogen overnight. The mixture is cooled to RT,concentrated in vacuo, and chromatographed on silica gel. The fractionsincluding the solid desired product are recrystallized twice fromisopropyl alcohol affording the desired product as a crystallinematerial, M.P.=230° C. (dec).

Calc'd. C, 63.73; H, 4.94; N, 18.

Found C, 63.84; H, 4.94; N, 18.30

The compounds of Formula I possess positive inotropic activity and areuseful as cardiotonic agents in the treatment of humans and othermammals for cardiac disorders including congestive heart failure. Theeffectiveness of the compounds of this invention a inotropic agents maybe determined by the following pharmacologic tests which evaluate thechange in cardiac contractile force upon exposure to a dose of saidcompounds. The ganglionic-beta blocked anesthetized dog procedure is onesuch standard test procedure; the inotropic results of this proceduregenerally correlate with the inotropic activity found in human patients.

Ganglionic-Beta Block Anesthetized Do Procedure

Adult mongrel dogs of either sex weighing 10 to 16 kg are fastedovernight, anesthetized with pentobarbital sodium 35 mg/kg, i.v.intubated, respired with room air using a Harvard respirator, andinstrumented surgically to monitor myocardial contractile force, heartrate, arterial pressure, aortic flow and EKG limb lead II. The aforesaidmeasurements are recorded continuously on a strip chart recorder.

Myocardial contractile force is monitored by a Walton-Brodie straingauge sutured to the left ventricular myocardium parallel to the leftanterior descending coronary artery. Arterial pressure is measured usinga fluid-filled catheter attached to a pressure transducer introduced viathe right femoral artery and positioned in the thoracic aorta. Meanarterial pressure is determined by electronically clamping the pulsatilepressure signal. Aortic flowis monitored using a precalibrated,noncanulating electromagnetic flow probe positioned around the thoracicaorta. Heart rate is monitored using a cardiotachometer triggered by theQRS complex of the limb lead II EKG. The right femoral vein iscannulated for intravenous infusion of drugs. Body temperature ismaintained at 37° C.

Following a 30 min postsurgical stabilization period, control valves arerecorded. Myocardial depression is induced by ganglionic and betareceptor blockade. Initially, the responsiveness of the autonomicnervous systems is assessed by performing a 30 sec bilateral carotidocclusion (BCO). Ten minutes later, a saline solution of isoproterenol0.3 mg/kg, i.v. is administered to assess beta receptor integrity. Tenminutes after that, a saline solution of mecamylamine 2 mg/kg, i.v. isinfused, followed by a saline solution of propranolol 1 mg/kg, i.v. plus0.3 mg/kg/hr. Twenty minutes later, a second BCO is performed todemonstrate ganglionic blockade followed by a second injection of salineisoproterenol 0.3 mg/kg, i.v. to demonstrate beta blockade. Ten minuteslater, the test compound or vehicle is administered intravenously inascending doses at 30 min intervals at 1.5 ml/min in a total volume of3.5 ml. On completion of the experiment, both BCO and isoproterenolchallenges are repeated to verify ganglionic and beta blockade.

The results of the blocked dog test show that compounds of the presentinvention increase contractile force and heart rate, and aortic bloodflow in a dose related manner while maintaining arterial pressure.

Additional test procedures which have been found to be an efficientmeans for ascertaining the inotropic activity of the compounds of thisinvention are described below.

Guinea Pig Atria Inotropic Screening Concentrations

Guinea pigs are stunned by a sudden blow to the head; their chests areopened and hearts excised and placed in Kreb's medium (concentrations,mM: NaCl, 118.39; KCl, 4.70;

MgSO₄, 1.18; KH₂ PO₄, 1.18; NaHCO₃, 25.00; glucose, 11.66 and CaCl₂,1.25 gassed with a mixture of 95% Ol₂. Left atria are removed andinserted into warmed (33° C) double jacketed tissue chambers containingoxygenated Kreb's medium (as above). The upper end of each tissue isattached to a Statham Universal Transducing Cell via a StathamMicroscale Accessory. Resting tension on each tissue is set at 1g andadjusted periodically.

Massive field stimulation is achieved via a pair of platinum or silverelectrodes placed on opposite sides of the tissue. Electrodes are madefrom 2-gauge silver wire wound into a tight coil approximately 12-14 mmin diameter. Electrodes are connected to a Grass stimulator via Grassconstant current unit. Tissues are driven at 90 pulses per minute with 5msec duration at current levels 20% greater than threshold forcontinuous beat.

Cumulative concentrations of test drugs are added to the tissue bath atintervals sufficient to allow developed tension to peak at a new level.

The increase in developed tension is each tissue for each compoundconcentration is measured, and the results are averaged and used toconstruct cumulative concentrationresponse curves. Slopes for theseregressions calculated via the method of Finney (1971) are comparedusing Student's t-test.

The following in vitro method is another means for measuring theinotropic potency of the present compounds. This method is amodification of the enzyme inhibition method reported by Thompson andAppleman (1970) and Thompson et al. (1974), and is believed to correlateto in vivo inotropic activity in humans.

Inhibition of Peak III cAMP Phosohodiesterase Activitv

The test compounds are included in media comprising a radioactivitylabeled substrate (³ H-cyclic nucleotide) such as adenosine3':5'-monophosphate (cyclic AMP) and quanine3':5'-nucleotidease isolatefrom a dog heart. The inhibition of the enzyme hydrolysis of the5'-nucleotide product of the cNUC-PDEase to the corresponding nucleosideis measured by separating the charged, unhydrolyzed substrate from theuncharged hydrolysis product. Separation may be achieved eitherchromatographically from the uncharged nucleoside product of the assaywith ion exchange resin so that it is not quantitated with the liquidscintillation counter.

Anesthetized Dog Procedure

Male mongrel dogs are anesthetized with pentobarb (35 mg/kg, i.v.) andintubated. Femoral artery and veins are cannulated for measurement ofblood pressure and injection of compounds, respectively. A catheterconnected to a Statham transducer is inserted into the left ventriclevia the right carotid artery for measurement of left ventricularpressure, left ventricular end diastolic pressure and dP/dt. Lead II ECGand heart rate are also monitored. All parameters are measured on aBeckman Dynagraph.

Two additional test procedures which have been found to be an efficientmeans for ascertaining the inotropic activity of the compounds of thisinvention are described below.

Conscious Instrumented Dog

Female mongrel dogs (18.0-18.5 kg) are anesthetized with sodiumpentobarbital (35 mg/kg, i.v., supplemented as necessary during surgery)intubated and connected to a Harvard respirator. The left side of thechest is opened at the fifth intercostal space, and a Konigsbergtransducer inserted into the left ventricle through a puncture at theapex and secured. A fluid-filled polyethylene catheter is inserted intothe left atrium through a puncture wound and secured for measurement ofleft atrial pressure. A second fluid-filled catheter is inserted intothe aorta for measurement of blood pressure and heart rate and securedto the vessel wall. The two catheters and the Konigsberg transducercable are passed out of the chest through the seventh intercostal spaceand advanced subcutaneously to the back of the neck and passed throughthe skin. The fluid-filled catheters are filled with heparinized 50%dextrose solution, and the chest is closed and evacuated.

The dog is trained and acclimated to its environment and the presence ofpersonnel during the experiment.

The dogs are fasted overnight before either intravenous or oraladministration of the compound. On a test day, the dog is placed in asling and connected to a recorder (Gould Instruments or GrassInstruments) for measurement of left ventricular pressure, leftventricular dP/dt_(m) ax, blood pressure, heart rate (from the bloodpressure signal), and the lead II electrocardiogram. The compound isadministered both intravenously and orally (liquid and soft gelatincapsule forms) in different experiments and blood samples were taken fordetermination of blood levels of the compound.

The compounds of this invention can be normally administered orally orparenterally, in the treatment of cardiac disorders such as heartfailure in humans or other mammals.

The compounds of this invention, preferably in the form of a salt, maybe formulated for administration in any convenient way, and theinvention includes within its scope pharmaceutical compositionscontaining at least one compound according to the invention adapted foruse in human or veterinary medicine. Such compositions may be formulatedin a conventional manner using one or more pharmaceutically acceptablecarriers or excipients. Suitable carriers include diluents or fillers,sterile aqueous media and various non-toxic organic solvents. Thecompositions may be formulated in the form of tablets, capsules,lozenges, troches, hard candies, powders, aqueous suspensions, orsolutions, injectable solutions, elixirs, syrups and the like and maycontain one or more agents selected from the group including sweeteningagents, flavoring agents, coloring agents and preserving agents, inorder to provide a pharmaceutically acceptable preparation.

The particular carrier and the ratio of inotropic active compound tocarrier are determined by the solubility and chemical properties of thecompounds, the particular mode of administration and standardpharmaceutical practice. For example, excipients such as lactose, sodiumcitrate, calcium carbonate and dicalcium phosphate and variousdisintegratants such as starch, alginic acid and certain complexsilicates, together with lubricating agents such as magnesium stearate,sodium lauryl; sodium lauryl sulphate and talc, can be used in producingtablets. For a capsule form, lactose and high molecular weightpolyethylene glycols are among the preferred pharmaceutically acceptablecarriers. Where aqueous suspensions for oral use are formulated, thecarrier can be emulsifying or suspending agents. Diluents such asethanol, propylene glycol, glycerin and chloroform and theircombinations can be employed as well as other materials.

For parenteral administration, solutions or suspensions of thesecompounds in sesame or peanut oil or aqueous propylene glycol solutions,as well as sterile aqueous solutions of the soluble pharmaceuticallyacceptable salts described herein can be employed. Solutions of thesalts of these compounds are especially suited for intramuscular andsubcutaneous injection purposes. The aqueous solutions, including thoseof the salts dissolved in pure distilled water, also useful forintravenous injection purposes, provided that their pH is properlyadjusted, suitably buffered, made isotonic with sufficient saline orglucose and sterilized by heating or by microfiltration.

The dosage regimen in carrying out the methods of this invention is thatwhich insures maximum therapeutic response until improvement is obtainedand thereafter the minimum effective level which gives relief. Thus, ingeneral, the dosages are those that are therapeutically effective inincreasing the contractile force of the heart or in the treatment ofcardiac failure. In general, the oral dose may be between about0.01mg/kg and about 50 mg/kg (preferably in the range of 0.1 to 10mg/kg), and the i.v. dose about I0 0.005 to about 30 mg/kg (preferablyin the range of 0.01 to 3 mg/kg), bearing in mind, of course, that inselecting the appropriate dosage in any specific case, considerationmust be given to the patient's weight, general health, age and otherfactors which may influence response to the drug. The drug may beadministered as frequently as is necessary to achieve and sustain thedesired therapeutic response. Some patients may respond quickly to arelatively large or small dose and require little or no maintenancedosage. On the other hand, other patients may require sustained dosingfrom about 1 to about 4 times a day depending on the physiological needsof the particular patient. Usually the drug may be administered orally 1to 4 times per day. It is anticipated that many patients will require nomore than about one to about two doses daily.

It is also anticipated that the present invention would be useful as aninjectable dosage form which may be administered in an emergency to apatient suffering from acute cardiac failure. Such treatment may befollowed by intravenous infusion of the active compound and the amountof compound infused into such a patient should be effective to achieveand maintain the desired therapeutic response.

We claim:
 1. A compound of the formula ##STR12## wherein: A is --C═ or--N═;B is --C═C--; --C═N-- or --N═C--; provided that A or B represents anitrogen-containing group; X is --(CR₄ R₅)_(a) --(O)_(b) -13 (CR₆R₇)_(c) --; a and c are 0, 1 or 2; b is 0 or 1; provided that a+b+c=1, 2or 3; R is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, nitro, halo,cyano, carbamoyl, alkyl carbamoyl, formyl aminoalkylene or amino; R₁,R₂, R₃, R₅, R₆ and R₇ are hydrogen, alkyl, or aralkyl; R₄ is hydrogen,alkyl, aryl, or aralkyl; geminal R₆ and R₇ groups may together form aspiro substituent, --(CH₂)_(d) --, where d is 2 to 5;or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 where R is cyano, R₂ is lower alkyl and R₁, R₃, R₄, R₅, R₆ andR₇ are hydrogen or lower alkyl.
 3. A compound according to claim 2whereR is cyano; R₁ is hydrogen; R₂ is methyl; and R₃, R₄, R₅, R₆ and R₇are hydrogen or methyl.
 4. A compound according to claim 3 whereA is--C═; B is --C═N--; and X is --O--CH₂ --.
 5. A compound according toclaim 3 whereA is --C═; B is --N═C--; and X is --O--CH₂ --.
 6. Acompound according to claim 3 whereA is --N═; B is --C═C--; and X is --O--CH₂ --.
 7. A compound according to claim 3 whereA is --C═; B is--C═N--; and X is --CH₂ --.
 8. A compound according to claim 3 whereA is--C═; B is --C═N--; and X is --O--.
 9. A compound according to claim 3whereA is --C═; B is --C═N--; and X is --0--CH₂ --CH₂ --.
 10. A compoundaccording to claim 1 where b is
 0. 11. A compound according to claim 10whereA is --C═; and B is --C═N--.
 12. A compound according to claim 11wherein a+c equals
 1. 13. A compound according to claim 11 wherein a+cequals
 2. 14. A compound according to claim 11 Wherein a+c equals
 3. 15.A compound according to claim 12 wherein c is 1 and geminal R₆ and R₇groups together form a spiro substituent.
 16. A compound according toclaim 11 wherein a=c=1 and geminal R₆ and R₇ groups together form aspiro substituent.
 17. A compound according to claim 4 which is7-[3,-cyano-6'-methyl-2'-oxo-(1)pyridin-5-yl]-4-ethyl-2H-pyrido[3,2-b]1,4-oxazin-3(4H)-oneor a pharmaceutically acceptable salt thereof.
 18. A compound accordingto claim 1 which is 7-[3,-cyano-6'-methyl-2'-oxo-(1H)pyridin-5,-yl]-2-phenyl-4-methyl-2H-pyrido[3,2-b ]-1,4-oxazin-3(4H)-oneor a pharmaceutically acceptable salt thereof.
 19. A compound accordingto claim 1 which is 8-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5,-yl]-5-methyl-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-oneor a pharmaceutically acceptable salt thereof.
 20. A compound accordingto claim 13 where R is cyano, R₂ is lower alkyl and R₁, R₃, R₄, R₅, R₆and R₇ are hydrogen or lower alkyl.
 21. A compound according to claim 11which is 6-[3,-cyano-6'-methyl-2'-oxo-(1H)pyridin-5,-yl]-3,4-dihydro-1-methyl-1,8-naphtheridin-2(1H)-one or apharmaceutically acceptable salt thereof.
 22. A method for increasingcardiotonic contractility in a patient requiring such treatment whichcomprises administering to such patient an effective amount of acompound according to claim
 1. 23. A pharmaceutical composition whereinthe active ingredient is a compound according to claim 1 in admixturewith a pharmaceutical carrier.